Epithelial cell glycoprotein MUC1 is overexpressed and hypoglycosylated on all human adenocarcinomas and is recognized by the immune system as a tumor antigen. In basic and preclinical studies supported by the long-standing grant that this application aims to renew, we have deciphered numerous interactions of MUC1 and the adaptive immune system and this knowledge has been translated to MUC1 based vaccines for pancreatic, breast, colon and prostate cancer. We also made an unexpected observation that MUC1 interacts directly with the cells of the innate immune system and thus might play an important role in inflammation and cancer. Our hypothesis is that overexpression and aberrant glycosylation of MUC1 promotes first chronic inflammation and later progression to cancer and thus MUC1 should be targeted not only for tumor therapy, as studied so far, but also for therapy of chronic inflammation before tumors develop. We propose two specific aims: Specific Aim 1. To define MUC1 related cellular and molecular events that regulate (induce, promote) chronic inflammation and cancer. We will use the new mouse model developed in the previous grant period as well as the information we obtained regarding the novel interactions of the MUC1 glycoprotein with the innate and the adaptive immune system. Specific Aim 2. To test the ability of MUC1-specific or MUC1-related immunotherapy to prevent chronic inflammation and cancer. We will use vaccines based on immunogenic MUC1 glycopeptides defined in the last grant period as well as MUC1 specific TCR transgenic mice developed in the same period. We have preliminary evidence that inducing MUC1 specific adaptive immunity can prevent not only cancer but also chronic inflammation. Nobody has yet considered MUC1 as a target for therapy, and specifically immunotherapy, of chronic inflammatory diseases that carry increased risk of cancer. PUBLIC HEALTH RELEVANCE: This is a long-standing project directed towards immunotherapy of cancer and cancer vaccines based on the tumor antigen MUC1. In this renewal application, work will be done to show that this form of immunotherapy and the same vaccines may be useful not only for cancer but also for treatment and prevention of chronic inflammations that increase risk for cancer.